Protein tyrosine phosphatases (PTPs) such as PTPN22, that encodes lymphoid tyrosine phosphatase (LYP), are important regulators of cell signalling. LYP, through interaction with various accessory molecules including Grb2 and Csk kinase, has been shown to be particularly important in regulating signal transduction from the T cell receptor. The identification of PTPN22 as a susceptibility locus for Graves disease (GD) led us to hypothesise that other PTPs may also influence GD onset. The newly discovered PTPN12, another PTP family member, has been shown to interact with the same T cell activation accessory molecules, Grb2 and Csk kinase, as LYP. PTPN12 was screened for association with GD in a large well characterised UK Caucasian case control cohort of 1056 GD and 854 controls using seven tagging single nucleotide polymorphisms (SNPs), which captured a further 40 SNPs within the gene and surrounding region. All subjects gave informed written consent and the project was approved by the local ethics committee. Genotyping of the seven tag SNPs using TaqMan® SNP genotyping chemistry revealed no individual associations (P=0.090.94). Preliminary correlations were performed between specific GD phenotypes and previously identified GD susceptibility loci. Three of the seven tag SNPs (rs1468682, rs4729535 and rs174672332) revealed significant association with the presence of ophthalmopathy (NOSPECS score 26) (P=0.050 0.025). Four SNPs (rs1468682, rs4729535, rs17155601 and rs174672332) revealed significant correlations with the previously associated thyrotropin hormone receptor (TSHR) rs2268458 SNP (P=0.030.002). Although no association was detected between individual PTPN12 tag SNPs, preliminary evidence suggests PTPN12 confers an increased risk of more severe ophthalmopathy (NOSPECS ≧2) and that PTPN12 interacts with the TSHR, which is not only the primary autoantigenic trigger for GD but also believed to play a role in the pathogenesis of ophthalmopathy. Replication of these data is now required to further validate our findings and justify additional analysis.